ClinVar Miner

Submissions for variant NM_005554.4(KRT6A):c.511A>G (p.Asn171Asp) (rs62635294)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000057007 SCV000322450 pathogenic not provided 2016-02-15 criteria provided, single submitter clinical testing The N171D variant in the KRT6A gene has been published previously in association with pachyonychia congenita (Liao et al., 2007; Bai et al., 2009). It was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The N171D variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution occurs within a known mutational hotspot region (helix initiation motif) that is highly conserved across all species and among all members of the keratin family. Many other pathogenic variants in patients with pachyonychia congenita have been reported at the same codon (N171Y/S/T/K) and in nearby residues (Q166P, I167S/N, L170F, F174V/I/C/S, S176P) according to the Human Gene Mutation Database (Stenson et al., 2014). Studies of the N171D variant in a humanized mouse model recapitulated the PC phenotype seen in human skin (García et al., 2011). It is well established that keratin gene mutations affecting the residues at the ends of the central rod domains of the keratin proteins (helix initiation and termination motifs) interfere with proper keratin intermediate filament assembly and function, resulting in hyperkeratosis and cell fragility (Chamcheu et al., 2011). In addition, the KRT6A gene has a low rate of benign missense variations. Therefore, we consider N171D to be pathogenic.
Epithelial Biology; Institute of Medical Biology, Singapore RCV000057007 SCV000088120 not provided not provided no assertion provided not provided
GeneReviews RCV000128818 SCV000172476 pathogenic Pachyonychia congenita 3 2014-07-24 no assertion criteria provided literature only

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